The development of antimicrobial resistance among Gram-negative pathogens poses a serious threat to global public health. Among several mechanisms of antibiotic resistance in Gram-negative bacteria, a major problem is the low permeability of their outer membranes that serve as barriers to prevent antibiotic uptake by passive diffusion. Thus, the development of methods to overcome this permeability-mediated resistance is an important therapeutic goal.
During the course of infection, most microbes assimilate physiologically essential iron by synthesizing and utilizing high affinity ferric ion chelators, called siderophores. The Fe(III)-siderophore complexes are recognized and active transport through the bacterial cell membrane is initiated via specific receptors. Attachment of antibiotics to siderophores produces potential “Trojan Horse” conjugates that may enter pathogenic bacteria via their iron uptake system, thereby circumventing the permeability-mediated drug resistance problem. While studies of both natural and artificial siderophore-drug conjugates (sideromycins) have demonstrated their potential for development of antimicrobial agents, additional studies are needed to develop sufficiently selective active agents. New siderophore mimics that have selective antibiotic activity are thus needed in the art.
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium that endangers immunocompromised patients, including those with cystic fibrosis (CF), cancer, or AIDS. Once the infection is established it is very difficult to eradicate because P. aeruginosa is intrinsically resistant to many of existing antibiotics, including β-lactams. Inadequate penetration through the cell envelope is a significant factor in the resistance of P. aeruginosa to β-lactam antibiotics such as ampicillin and amoxicillin.
Like many other types of bacteria, strains of P. aeruginosa have developed receptors to recognize and transport Fe(III)-siderophore complexes from other species (xenosiderophores) in order to gain a competitive growth advantage. Enterobactin is a tris-catecholate siderophore primarily found in Gram-negative bacteria, such as Escherichia coli and Salmonella typhimurium. Enterobactin can also promote iron uptake into P. aeruginosa and the uptake is specifically inducible by enterobactin under iron-limiting conditions. Using enterobactin as a shuttle to deliver antibiotics into P. aeruginosa and other producing bacteria is an attractive strategy to pursue. However, this approach would be synthetically challenging because enterobactin has no functionality or site suitable for drug conjugation. Thus, new siderophore conjugates are needed to advance the study of antibiotic selectivity and to provide antibiotics effective against drug-resistant bacteria.